TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer

  • Nat Cancer. 2021 Nov;2(11):1185-1203. doi: 10.1038/s43018-021-00258-w.
Mengyu Tu  #  1 ,  Lukas Klein  #  1 ,  Elisa Espinet  2  3 ,  Theodoros Georgomanolis  4 ,  Florian Wegwitz  5 ,  Xiaojuan Li  6 ,  Laura Urbach  1 ,  Adi Danieli-Mackay  7 ,  Stefan Küffer  7 ,  Kamil Bojarczuk  8 ,  Athanasia Mizi  7 ,  Ufuk Günesdogan  6 ,  Björn Chapuy  8 ,  Zuguang Gu  9  10 ,  Albrecht Neesse  1 ,  Uday Kishore  11 ,  Philipp Ströbel  7 ,  Elisabeth Hessmann  1 ,  Stephan A Hahn  12 ,  Andreas Trumpp  2  3 ,  Argyris Papantonis  7 ,  Volker Ellenrieder  1 ,  Shiv K Singh  13
Affiliations
  • 1. Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Germany.
  • 2. Division of Stem Cells and Cancer, DKFZ, Heidelberg, Germany.
  • 3. Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbh), Heidelberg, Germany.
  • 4. Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • 5. Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.
  • 6. Department of Developmental Biology, Göttingen Center for Molecular Biosciences, Göttingen, Germany.
  • 7. Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
  • 8. Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
  • 9. Bioinformatics and Omics Data Analytics, DKFZ, Heidelberg, Germany.
  • 10. Division of Cancer Epigenomics, DKFZ, Heidelberg, Germany.
  • 11. Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK.
  • 12. Faculty of Medicine, Department of Molecular GI Oncology, Ruhr University Bochum, Bochum, Germany.
  • 13. Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Germany. [email protected].
  • # Contributed equally.
PMID: 35122059 DOI: 10.1038/s43018-021-00258-w
Abstract

Large-scale genomic profiling of pancreatic Cancer (PDAC) has revealed two distinct subtypes: 'classical' and 'basal-like'. Their variable coexistence within the stromal immune microenvironment is linked to differential prognosis; however, the extent to which these neoplastic subtypes shape the stromal immune landscape and impact clinical outcome remains unclear. By combining preclinical models, patient-derived xenografts, as well as FACS-sorted PDAC patient biopsies, we show that the basal-like neoplastic state is sustained via BRD4-mediated cJUN/AP1 expression, which induces CCL2 to recruit tumor necrosis factor (TNF)-α-secreting macrophages. TNF-α+ macrophages force classical neoplastic cells into an aggressive phenotypic state via lineage reprogramming. Integration of ATAC-, ChIP- and RNA-seq data revealed distinct JUNB/AP1 (classical) and cJUN/AP1 (basal-like)-driven regulation of PDAC subtype identity. Pharmacological inhibition of BRD4 led to suppression of the BRD4-cJUN-CCL2-TNF-α axis, restoration of classical subtype identity and a favorable prognosis. Hence, patient-tailored therapy for a cJUNhigh/TNF-αhigh subtype is paramount in overcoming highly inflamed and aggressive PDAC states.

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